The blood-brain barrier (BBB) is a highly selective permeability barrier that separates the circulating blood in the brain from the central nervous system and which functions to shield the brain from harmful elements in the blood and cerebrospinal fluid (CSF), while facilitating the exchange of essential amino acids, ions, metabolites, neurotransmitters, oxygen, carbon dioxide, growth factors, and other necessary nutrients and cellular wastes within the brain tissue. Although the BBB has evolved to effectively regulate brain homeostasis and to protect the brain from the harmful effects of unwanted elements in the blood and CSF, such as toxins and bacteria, the BBB also presents a significant challenge in the context of delivering therapeutic agents to the brain. Therapeutic molecules and antibodies that might otherwise be effective in diagnosis and therapy do not generally cross the BBB in adequate amounts to be effective in treatment. Overcoming the difficulty of delivering such therapeutics—ranging from small molecules, protein therapeutics and antibodies, and nucleic acids—presents a major challenge in the treatment of most brain disorders, including brain cancer and tumors, stroke, Alzheimer's disease, and dementia.
A variety of approaches have been explored to improve the efficacy of drug delivery to the brain such that effective treatments may be administered. Mechanisms for drug targeting in the brain involve going either “through” or “behind” the BBB. For example, methods for drug delivery through the BBB can involve biochemical means, i.e., by the use of vasoactive substances, such as bradykinin. Other modalities can include localized exposure to high-intensity focused ultrasound (HIFU). However, such an approach leaves a long-term opening and as such, leaves the brain vulnerable to infection and toxins. Still other methods may entail the use of endogenous transport systems, including carrier-mediated transporters, such as glucose and amino acid carriers or receptor-mediated transcytosis. In addition, modalities may include active blocking of efflux transporters. Methods may also include intracerebral implantations, such as with needles, and convection-enhanced distribution.
One well-known, yet problematic strategy to move desired drugs into the brain is to physically disrupt the BBB with hyperosmolar agents. The disruption to the BBB allows makes it possible for drugs or desired therapeutic agents to diffuse the brain parenchym through the compromised BBB. Osmotic disruption typically uses a concentrated dose of mannitol to remove fluid from the brain's endothelial cells, which causes them to shrink, thereby opening the tight endothelial cell junctions. The disadvantage in this approach is that BBB disruption also weakens the natural protective function of the BBB against bacterial infections and/or toxins. In addition, this approach sees highly results due in part to the high unpredictability and/or lack of control as to the particular the location and range of the BBB disruption that results from the hyperosmolar agent. This lack of predictability in knowing the territory of the BBB opening significantly limits the ability to achieve highly targeted intra-arterial drug administrations. Thus, despite its discovery over 40 years ago, hyperosmotic BBB opening (BBBO) remains highly variable, preventing its widespread implementation.
Accordingly, there is an unmet need for improved methods of intra-arterial drug administration in the brain that provides reproducible and highly selective delivery of drugs to the brain for treating a wide array of disorders, including cancer and neurodegenerative disorders.